Method of synthesis of substituted hexitols such as dianhydrogalactitol

ABSTRACT

The present invention provides an efficient method of synthesizing and purifying dianhydrohexitols such as dianhydrogalactitol. In general, as applied to dianhydrogalactitol, the method comprises: (1) reacting dulcitol with a concentrated solution of hydrobromic acid at a temperature of about 80° C. to produce dibromogalactitol; (2) reacting the dibromogalactitol with potassium carbonate in t-butanol to produce dianhydrogalactitol; and (3) purifying the dianhydrogalactitol using a slurry of ethyl ether to produce purified dianhydrogalactitol. Another method produces dianhydrogalactitol from dulcitol; this method comprises: (1) reacting dulcitol with a reactant to convert the 1,6-hydroxy groups of dulcitol to an effective leaving group to generate an intermediate; and (2) reacting the intermediate with an inorganic weak base to produce dianhydrogalactitol through an intramolecular S N 2 reaction. Other methods for the synthesis of dianhydrogalactitol from dulcitol are described.

CROSS-REFERENCES

This application claims the benefit and is a continuation-in-part ofU.S. patent application Ser. No. 13/933,751, by Dennis M. Brown, Ph.D.,filed Jul. 2, 2013, and entitled “Method of Synthesis of SubstitutedHexitols Such as Dianhydrogalactitol,” which in turn claimed the benefitand is a continuation-in-part of U.S. patent application Ser. No.13/817,046, by Dennis M. Brown, Ph.D., filed Feb. 14, 2013, and entitled“Method of Synthesis of Substituted Hexitols Such asDianhydrogalactitol,”, which in turn claimed the benefit of PCTApplication Serial No. PCT/US2011/048032, by Dennis M. Brown, Ph.D.,filed Aug. 17, 2011, designating the United States, and entitled “Methodof Synthesis of Substituted Hexitols Such as Dianhydrogalactitol,” whichin turn claimed the benefit of U.S. Provisional Application Ser. No.61/401,710, by Dennis M. Brown, Ph.D., filed Aug. 18, 2010, and entitled“Method of Synthesis of Substituted Hexitols Such asDianhydrogalactitol.” These four applications are incorporated herein intheir entirety by this reference.

TECHNICAL FIELD OF THE INVENTION

The present invention is directed to improved methods for the synthesisof substituted hexitols, especially dianhydrogalactitol.

BACKGROUND OF THE INVENTION

A number of substituted hexitols, such as dianhydrogalactitol, havepharmacological activities. In particular, dianhydrogalactitol has beensuggested for use in chemotherapy, such as in U.S. Pat. No. 7,157,059 toNielsen et al., incorporated herein by this reference.

However, current methods of synthesis of such substituted hexitols, suchas dianhydrogalactitol, are inefficient, and improved methods ofsynthesis of these substituted hexitols are required in order to providelarger quantities of these compounds for clinical use.

SUMMARY OF THE INVENTION

An improved method of synthesis of dianhydrohexitols such asdianhydrogalactitol comprises conversion of the hexitol to adibromohexitol by reaction with concentrated hydrobromic acid, followedby conversion of the dibromohexitol to the dianhydrohexitol by reactionwith potassium carbonate.

In general, as applied to the synthesis of dianhydrogalactitol, themethod comprises the steps of:

(1) reacting dulcitol with a concentrated solution of hydrobromic acidat a temperature of about 80° C. to produce dibromogalactitol;

(2) reacting the dibromogalactitol with potassium carbonate in t-butanolto produce dianhydrogalactitol; and

(3) purifying the dianhydrogalactitol using a slurry of ethyl ether toproduce purified dianhydrogalactitol.

In this method, typically, the concentrated solution of hydrobromic acidis about 70% hydrobromic acid and is produced by reacting phosphoruswith bromine in hydrobromic acid at elevated temperature. Typically, thedibromogalactitol is dissolved in t-butanol in a proportion of about 1 gof dibromogalactitol to 10 mL of t-butanol.

In this method, typically, the dulcitol is purified from the plantMaytenus confertiflora by the steps of:

-   -   (a) soaking the plant Maytenus confertiflora in a soaking        solution of from about 50% to about 80% of ethanol for about 24        hours;    -   (b) collecting the soaking solution from step (a);    -   (c) repeating the soaking step of step (a) with a fresh soaking        solution of from about 50% to about 80% of ethanol for about 24        hours;    -   (d) collecting the soaking solution from step (c) and combining        it with the soaking solution collected in step (b);    -   (e) removing the solvent from the combined soaking solutions of        step (d) by heating under reduced pressure to produce a        concentrated solution;    -   (f) allowing the concentrated solution of step (e) to settle        overnight and collecting the clear supernatant;    -   (g) extracting the clear supernatant from step (f) with        chloroform and then removing the chloroform under heat and        reduced pressure;    -   (h) dissolving the residue from step (g) in hot methanol and        then cooling to allow crystallization; and    -   (i) collecting the collected crystals of dulcitol, filtering,        and drying the crystals under reduced pressure.

Although this method is described for the synthesis and purification ofdianhydrogalactitol, it is not limited to dianhydrogalactitol, and canbe applied to other hexitols bearing two epoxide groups such assubstituted dianhydrogalactitols.

More generally, a method according to the present invention forsynthesizing and purifying a dianhydrohexitol comprises the steps of:

(1) reacting a hexitol bearing two epoxide groups with a concentratedsolution of hydrobromic acid at a temperature of about 80° C. to producea dibromohexitol;

(2) reacting the dibromohexitol with a carbonate salt of an alkali metalin a tertiary alcohol to produce a dianhydrohexitol; and

(3) purifying the dianhydrohexitol using a slurry of an ether to producethe purified dianhydrohexitol.

Typically, the dianhydrohexitol is selected from the group consisting ofdianhydrogalactitol and a substituted dianhydrogalactitol. Preferably,the dianhydrohexitol is dianhydrogalactitol.

Typically, the concentrated solution of hydrobromic acid is about 70%hydrobromic acid and is produced by reacting phosphorus with bromine inhydrobromic acid at elevated temperature.

Typically, the tertiary alcohol is selected from the group consisting oft-butanol, 2-methyl-2-butanol, and 3-ethylpentanol. Preferably, thetertiary alcohol is t-butanol.

Typically, the dibromohexitol is dissolved in the tertiary alcohol in aproportion of about 1 g of dibromohexitol to 10 mL of tertiary alcohol.

Typically, the dibromohexitol is purified by recrystallization prior toits conversion to dianhydrohexitol.

Typically, the carbonate salt of the alkali metal is a carbonate salt ofan alkali metal selected from the group consisting of sodium carbonateand potassium carbonate. Preferably, the carbonate salt of the alkalimetal is potassium carbonate.

Typically, the ether is an aliphatic ether with lower alkyl groups.Preferably, the ether is selected from the group consisting of dimethylether, methyl ethyl ether, diethyl ether, dipropyl ether, methyl propylether, and ethyl propyl ether. More preferably, the ether is diethylether.

Other methods for the synthesis of dianhydrogalactitol are described. Ingeneral, these methods start with dulcitol.

In one alternative, the method comprises:

(1) reacting dulcitol with a reactant to convert the 1,6-hydroxy groupsof dulcitol to an effective leaving group to generate an intermediate;and

(2) reacting the intermediate with an inorganic weak base to producedianhydrogalactitol through an intramolecular S_(N)2 reaction.

Typically, the effective leaving group of step (1) is selected from thegroup consisting of Br, OTf (triflate or trifluoromethane sulfonate),and OTs (tosylate). Preferably, the effective leaving group of step (1)is Br.

In one alternative, the intermediate of step (1) is prepared by:

-   -   (a) using 45-48% aqueous hydrobromic acid with the addition of        phosphorus and Br₂ to generate a 60-70% solution of hydrobromic        acid, then adding dulcitol and reacting at 70° C. for 5-7 hours;    -   (b) cooling the reaction mass of (i) to room temperature and        pouring into ice water to obtain the crude intermediate of step        (1); and    -   (c) recrystallizing using a polar solvent without a nucleophilic        property.

In another alternative, the intermediate of step (1) is prepared by:

-   -   (a) adding dulcitol to a 62% aqueous hydrobromic acid solution        and reacting at 70° C. for 5-7 hours;    -   (b) cooling the reaction mass of (a) to room temperature and        pouring into ice water to obtain the crude intermediate of step        (1); and    -   (c) recrystallizing using a polar solvent without a nucleophilic        property.

In yet another alternative, the intermediate of step (1) is prepared by:

-   -   (a) adding dulcitol to a 33% HBr solution in acetic acid and        mixing for 5-7 hours at room temperature;    -   (b) adding methanol and mixing for 15 hours;    -   (c) concentrating under vacuum to remove most of the solvent;    -   (d) recrystallizing using a polar solvent without a nucleophilic        property.

In still another alternative, the intermediate of step (1) is preparedby:

-   -   (a) dissolving dulcitol in pyridine or dimethylformamide (DMF)        at room temperature;    -   (b) adding CBr₄ and Ph₃P in sequence and mixing for 15-18 hours        at room temperature;    -   (c) after the completion of the reaction of step (ii),        concentrating under vacuum to remove solvent and chloroform        formed from the reaction;    -   (d) washing the remaining solid several times with        dichloromethane to remove triphenylphosphine byproduct; and    -   (e) recrystallizing using a polar solvent without a nucleophilic        property. Typically, in this alternative, the dulcitol is        dissolved in pyridine. Alternatively, the dulcitol is dissolved        in dimethylformamide.

Typically, the polar solvent without a nucleophilic property is selectedfrom the group consisting of 2-chloromethane/t-butanol and2-chloromethane/isopropyl alcohol.

When the effective leaving group of step (1) is selected from the groupconsisting of OTf (triflate or trifluoromethane sulfonate) and OTs(tosylate), typically, the intermediate is generated by:

-   -   (a) dissolving dulcitol in pyridine;    -   (b) adding TsCl or Tf₂O at 0° C. and mixing for 15-18 hours;    -   (c) after the completion of the reaction, concentrating under        vacuum to remove solvent;    -   (d) pouring the remaining solution into ice water to obtain the        intermediate; and    -   (e) recrystallizing using a polar solvent without a nucleophilic        property.

In one alternative, the intermediate is converted to DAG using K₂CO₃ andt-BuOH.

In another alternative, the intermediate is converted to DAG using aninorganic alkali in a polar nonionic solvent. In this alternative,typically, the intermediate is converted to DAG employing a process withthe steps of:

-   -   (a) dissolving the intermediate in the polar nonionic solvent;    -   (b) adding an inorganic carbonate and mixing at room temperature        for 5-7 hours;    -   (c) after the completion of the reaction of step (ii), adding        p-toluenesulfonic acid to neutralize the inorganic carbonate;    -   (d) concentrating under vacuum to remove the solvent;    -   (e) washing the remaining solid with water to remove impurities;    -   (f) adding ether to the crude material of step (v); and    -   (g) filtering the slurry to obtain DAG.

Typically, the inorganic carbonate is selected from the group consistingof K₂CO₃ and CS₂CO₃. Preferably, the inorganic carbonate is K₂CO₃.Typically, the polar nonionic solvent is dimethylformamide (DMF).

Another aspect of the invention is a method for synthesizingdianhydrogalactitol (DAG) comprising the steps of:

-   -   (1) substituting the 1,6-hydroxyl groups of dulcitol with        bromine;    -   (2) substituting the hydroxyl groups of dulcitol other than the        1,6-hydroxyl groups with acetyl groups to yield an intermediate        in which the 1,6-hydroxyl groups of dulcitol are substituted        with bromine and the hydroxyl groups of dulcitol other than the        1,6-hydroxyl groups are substituted with acetyl groups;    -   (3) reacting the intermediate of step (2) with zinc in the        presence of an organic base to form double bonds through an        elimination reaction;    -   (4) removing the protective acetyl groups; and    -   (5) forming dianhydrogalactitol by the Sharpless epoxidation        reaction.

Typically, the organic base is sodium methoxide. Typically, thesubstitution of the 1,6 hydroxy groups is performed with reaction withacetyl bromide. Typically, the acetylation of the hydroxy groups otherthan the 1,6-hydroxy groups is performed with acetic anhydride inpyridine.

Yet another method for the production of dianhydrogalactitol fromdulcitol provides recrystallized dianhydrogalactitol of high quality.This method is suitable for scaling up and for the production of largequantities of recrystallized dianhydrogalactitol. This method can beapplied to other hexitols.

In general, as applied to the synthesis of a dianhydrohexitol, themethod comprises the steps of:

(1) converting a hexahydroxyl-substituted sugar alcohol to a dibromoderivative of the hexahydroxyl-substituted sugar alcohol by reaction ofthe dulcitol with hydrobromic acid for from about 18 hours to about 36hours at an elevated temperature;

(2) adding the product of step (1) to water, agitating the product ofstep (1) added to water for from about 18 hours to about 36 hours,filtering the mixture of the product of step (1) and water, washing themixture with a large volume of water, drying the solid product undernitrogen, and then subsequently washing the dried solid product with alarge volume of an aliphatic ether;

(3) reacting the product of step (b) with a carbonate of an alkali metalin a polar aprotic solvent at an elevated temperature;

(4) filtering the product of step (3) to remove the solids;

(5) washing the solids removed in step (4) with a polar aprotic solventand combining the washings with the solids removed in step (4);

(6) concentrating the combination of the washings with the solids ofstep (5) to a volume that is approximately from about 0.20 to about 0.27of the volume of polar aprotic solvent used in step (3) at a temperatureof from about 30° C. to about 40° C.;

(7) agitating the concentrated product of step (6) for from about 18hours to about 36 hours at a temperature of from about 0° C. to about10° C.;

(8) washing the product of step (7) with an aliphatic ether;

(9) drying the washed product of step (8) under nitrogen; and

(10) recrystallizing the product of step (9) by:

-   -   (a) dissolving the product of step (9) in acetone;    -   (b) filtering off insoluble solids remaining after dissolving        the product of step (9) in acetone;    -   (c) concentrating the solution of step (10)(a) down to a volume        of about 0.07 to about 0.12 of the original volume of acetone;    -   (d) cooling the concentrated solution of step (10)(c) to about        −20° C. to generate solid recrystallized dianhydrohexitol and        agitating the suspension of solid recrystallized        dianhydrohexitol for from about 18 hours to about 36 hours;    -   (e) filtering the solids of step (10)(d) and washing the solids        with a large volume of an aliphatic ether; and    -   (f) drying the washed solids of step (10)(e) under nitrogen to        produce a solid recrystallized dianhydrohexitol.

In general, as applied to dianhydrogalactitol, this method comprises thesteps of:

(1) converting dulcitol to dibromodulcitol by reaction of the dulcitolwith hydrobromic acid for from about 18 hours to about 36 hours at anelevated temperature;

(2) adding the product of step (a) to water, agitating the product ofstep (1) added to water for from about 18 hours to about 36 hours,filtering the mixture of the product of step (1) and water, washing themixture with a large volume of water, drying the solid product undernitrogen, and then subsequently washing the dried solid product with alarge volume of an aliphatic ether;

(3) reacting the product of step (2) with a carbonate of an alkali metalin a polar aprotic solvent at an elevated temperature;

(4) filtering the product of step (3) to remove the solids;

(5) washing the solids removed in step (4) with a polar aprotic solventand combining the washings with the solids removed in step (4);

(6) concentrating the combination of the washings with the solids ofstep (5) to a volume that is approximately from about 0.20 to about 0.27of the volume of polar aprotic solvent used in step (3) at a temperatureof from about 30° C. to about 40° C.;

(7) agitating the concentrated product of step (6) for from about 18hours to about 36 hours at a temperature of from about 0° C. to about10° C.;

(8) washing the product of step (7) with an aliphatic ether;

(9) drying the washed product of step (8) under nitrogen; and

(10) recrystallizing the product of step (9) by:

-   -   (a) dissolving the product of step (9) in acetone;    -   (b) filtering off insoluble solids remaining after dissolving        the product of step (9) in acetone;    -   (c) concentrating the solution of step (10)(a) down to a volume        of about 0.07 to about 0.12 of the original volume of acetone;    -   (d) cooling the concentrated solution of step (10)(c) to about        −20° C. to generate solid recrystallized dianhydrogalactitol and        agitating the suspension of solid recrystallized        dianhydrogalactitol for from about 18 hours to about 36 hours;    -   (e) filtering the solids of step (10)(d) and washing the solids        with a large volume of an aliphatic ether; and    -   (f) drying the washed solids of step (10)(e) under nitrogen to        produce solid recrystallized dianhydrogalactitol.

Typically, the elevated temperature of step (1) is from about 35° C. toabout 45° C. Preferably, the elevated temperature of step (1) is about40° C.

Typically, in step (1), the dulcitol is reacted with hydrobromic acidfrom about 18 hours to about 24 hours.

Typically, the aliphatic ether of step (2) is selected from the groupconsisting of methyl t-butyl ether, dimethyl ether, methyl ethyl ether,diethyl ether, dipropyl ether, methyl propyl ether, and ethyl propylether. Preferably, the aliphatic ether of step (2) is methyl t-butylether.

Typically, in step (2), the mixture of the product of step (1) added towater is agitated for about 24 hours.

Typically, the polar aprotic solvent of step (3) is tetrahydrofuran.Typically, the carbonate of the alkali metal of step (3) is selectedfrom the group consisting of lithium carbonate, sodium carbonate, andpotassium carbonate. Preferably, the carbonate of the alkali metal ofstep (3) is potassium carbonate. Typically, the elevated temperature ofstep (3) is from about 35° C. to about 45° C. Preferably, the elevatedtemperature of step (3) is about 40° C.

Typically, the temperature of step (6) is about 35° C.

Typically, the temperature of step (7) is about 4° C. Typically, in step(7), the concentrated product of step (6) is agitated for about 24hours.

Typically, the aliphatic ether of step (8) is selected from the groupconsisting of methyl t-butyl ether, dimethyl ether, methyl ethyl ether,diethyl ether, dipropyl ether, methyl propyl ether, and ethyl propylether. Preferably, the aliphatic ether of step (8) is methyl t-butylether.

Typically, in step (10)(c), the solution of step (10)(a) is concentrateddown to about 0.09 of the original volume of acetone. Typically, theagitation of step (10)(d) is performed for about 24 hours.

Typically, the aliphatic ether of step (10)(e) is selected from thegroup consisting of methyl t-butyl ether, dimethyl ether, methyl ethylether, diethyl ether, dipropyl ether, methyl propyl ether, and ethylpropyl ether. Preferably, the aliphatic ether of step (10)(e) is methylt-butyl ether.

Typically, the drying of step (10)(f) is performed for a minimum ofabout 18 hours.

Typically, the recrystallized dianhydrogalactitol produced by the methoddescribed above, with steps (1)-(10), has total impurities of less thanabout 0.65%. Typically, the recrystallized dianhydrogalactitol producedby the method described above, with steps (1)-(10), has no detectableacetic acid, tetrahydrofuran, or methyl t-butyl ether. Typically, therecrystallized dianhydrogalactitol produced by the method describedabove, with steps (1)-(10), has residual acetone of less than about0.15%. Typically, the recrystallized dianhydrogalactitol produced by themethod described above, with steps (1)-(10), has a water content of lessthan about 2.15%.

Another aspect of the invention is purified recrystallizeddianhydrogalactitol produced by the method described above, with steps(1)-(10). Typically, the purified recrystallized dianhydrogalactitol hastotal impurities of less than about 0.65%. Typically, the purifiedrecrystallized dianhydrogalactitol has no detectable acetic acid,tetrahydrofuran, or methyl t-butyl ether. Typically, the purifiedrecrystallized dianhydrogalactitol has residual acetone of less thanabout 0.15%. Typically, the purified recrystallized dianhydrogalactitolhas a water content of less than about 2.15%.

DETAILED DESCRIPTION OF THE INVENTION

Dianhydrogalactitol (DAG) can be synthesized from dulcitol which can beproduced from natural sources (such as Maytenus confertiflora) orcommercial sources.

The structure of DAG is given below as Formula (I).

One method for the preparation of dulcitol from Maytenus confertiflorais as follows: (1) The Maytenus confertiflora plant is soaked in dilutedethanol (50-80%) for about 24 hours, and the soaking solution iscollected. (2) The soaking step is repeated, and all soaking solutionsare combined. (3) The solvent is removed by heating under reducedpressure. (4) The concentrated solution is allowed to settle overnightand the clear supernatant is collected. (5) Chloroform is used toextract the supernatant. The chloroform is then removed under heat andreduced pressure. (6) The residue is then dissolved in hot methanol andcooled to allow crystallization. (7) The collected crystals of dulcitolare filtered and dried under reduced pressure. The purified material isdulcitol, contained in the original Maytenus confertiflora plant at aconcentration of about 0.1% ( 1/1000).

In one alternative, DAG can be prepared by two general synthetic routesas described below:

In Route 1, “Ts” represents the tosyl group, or p-toluenesulfonyl group.

However, the intermediate of Route 1, 1,6-ditosyldulcitol, was preparedwith low yield (˜36%), and the synthesis of 1,6-ditosyldulcitol waspoorly reproducible. Therefore, the second route process was developed,involving two major steps: (1) preparation of dibromodulcitol fromdulcitol; and (2) preparation of dianhydrodulcitol from dibromodulcitol.

Dibromodulcitol is prepared from dulcitol as follows: (1) With anaqueous HBr solution of approximately 45% HBr concentration, increasethe HBr concentration to about 70% by reacting phosphorus with brominein concentrated HBr in an autoclave. Cool the solution to 0° C. Thereaction is: 2P+3Br₂→2PBr₃+H₂O→HBr↑+H₃PO₄. (2) Add the dulcitol to theconcentrated HBr solution and reflux at 80° C. to complete the reaction.(3) Cool the solution and pour the mixture onto ice water.Dibromodulcitol is purified through recrystallization.

The results for the preparation of dibromodulcitol (DBD) are shown inTable 1, below.

TABLE 1 Dulcitol 18 g 18 g 18 g 18 g 45% aq. HBr 36 mL 36 mL 36 mL 36 mLPBr₃ 40 g 40 g 40 g 40 g Time 7 h 7 h 7 h 7 h Temp/° C. 70 70 70 70Crude Product 25.2 g 25.5 g 24 g 24.7 g Yield 84% 85% 80% 82%

For the preparation of DAG from DBD, DBD was poorly dissolved inmethanol and ethanol at 40° C. (different from what was described inU.S. Pat. No. 3,993,781 to Horvath nee Lengyel et al., incorporatedherein by this reference). At refluxing, DBD was dissolved but TLCshowed that new impurities formed that were difficult to remove fromDBD.

The DBD was reacted with potassium carbonate to convert the DBD todianhydrogalactitol.

The results are shown in Table 2, below.

TABLE 2 DBD 0.5 g 5 g 4.3 g K₂CO₃ 1 g 8 g 4 g t-BuOH 5 mL 50 mL 40 mLDAG 0.17 g 1 g 0.82 g Yield 72% 42% 40%

In the scale-up development, it was found the crude yield droppedsignificantly. It is unclear if DAG could be azeotropic with BuOH. Itwas confirmed that t-BuOH is essential to the reaction. Using MeOH assolvent would result in many impurities as shown spots on TLC. However,an improved purification method was developed by using a slurry withethyl ether, which could provide DAG with good purity. This wasdeveloped after a number of failed attempts at recrystallization of DAG.

Accordingly, one aspect of the present invention is a method forsynthesizing and purifying dianhydrogalactitol (DAG) comprising thesteps of:

(1) reacting dulcitol with a concentrated solution of hydrobromic acidat a temperature of about 80° C. to produce dibromogalactitol;

(2) reacting the dibromogalactitol with potassium carbonate in t-butanolto produce dianhydrogalactitol; and

(3) purifying the dianhydrogalactitol using a slurry of ethyl ether toproduce purified dianhydrogalactitol.

In this method, typically, the concentrated solution of hydrobromic acidis about 70% hydrobromic acid and is produced by reacting phosphoruswith bromine in hydrobromic acid at elevated temperature. Typically, thedibromogalactitol is dissolved in t-butanol in a proportion of about 1 gof dibromogalactitol to 10 mL of t-butanol. Typically, thedibromogalactitol is purified by recrystallization prior to itsconversion to dianhydrogalactitol.

In this method, typically, the dulcitol is purified from the plantMaytenus confertiflora by the steps of:

-   -   (a) soaking the plant Maytenus confertiflora in a soaking        solution of from about 50% to about 80% of ethanol for about 24        hours;    -   (b) collecting the soaking solution from step (a);    -   (c) repeating the soaking step of step (a) with a fresh soaking        solution of from about 50% to about 80% of ethanol for about 24        hours;    -   (d) collecting the soaking solution from step (c) and combining        it with the soaking solution collected in step (b);    -   (e) removing the solvent from the combined soaking solutions of        step (iv) by heating under reduced pressure to produce a        concentrated solution;    -   (f) allowing the concentrated solution of step (e) to settle        overnight and collecting the clear supernatant;    -   (g) extracting the clear supernatant from step (f) with        chloroform and then removing the chloroform under heat and        reduced pressure;    -   (h) dissolving the residue from step (g) in hot methanol and        then cooling to allow crystallization; and    -   (i) collecting the collected crystals of dulcitol, filtering,        and drying the crystals under reduced pressure.

Another embodiment of the invention is a method for synthesizing andpurifying a dianhydrohexitol comprising the steps of:

(1) reacting a hexitol bearing two epoxide groups with a concentratedsolution of hydrobromic acid at a temperature of about 80° C. to producea dibromohexitol;

(2) reacting the dibromohexitol with a carbonate salt of an alkali metalin a tertiary alcohol to produce a dianhydrohexitol; and

(3) purifying the dianhydrohexitol using a slurry of an ether to producethe purified dianhydrohexitol.

In this method, the dianhydrohexitol can be, for example,dianhydrogalactitol or another dianhydrohexitol that has two epoxidegroups, such as a substituted dianhydrogalactitol, as described above.However, typically the dianhydrohexitol is dianhydrogalactitol.

In this method, the carbonate salt of the alkali metal is typically acarbonate salt of an alkali metal selected from the group consisting ofsodium carbonate and potassium carbonate. Preferably, the carbonate saltof the alkali metal is potassium carbonate.

In this method, the tertiary alcohol is typically t-butanol; however,other tertiary alcohols can be alternatively employed. Such tertiaryalcohols include, for example, 2-methyl-2-butanol, 3-ethylpentanol, andother tertiary alcohols, typically containing 6 carbons or fewer.

In this method, the debromination step (step (2) above) occurs underrefluxing conditions, which means that, when the tertiary alcohol ist-butanol, which has a boiling point of 82° C., reflux temperature wouldbe about 80-85° C.

In this method, in the step of purifying the dianhydrohexitol from theether slurry (step (3) above), the ether is typically an aliphatic etherwith lower alkyl groups, such as dimethyl ether, methyl ethyl ether,diethyl ether, dipropyl ether, methyl propyl ether, and ethyl propylether. However, a preferable ether is diethyl ether.

Additional alternatives for the synthesis of dianhydrogalactitol aredescribed. In general, in these alternatives, dianhydrogalactitolsynthesis involves three major steps: (1) preparation of dibromodulcitol(DBD) from a commercial source of dulcitol; (2) preparation ofdianhydrogalactitol (DAG) from DBD; and (3) recrystallization to purifythe DAG.

The specific process for each step is described below:

For the preparation of DBD, the reaction is as shown in Scheme 1 (Step1), below:

Hydrobromic acid (33% HBr in acetic acid, 2.1 eq) was added to 50 g ofdulcitol (1 eq) and mixed. The mixture was then heated to 40° C. andmixed for 18 hours yielding a turbid suspension. The suspension wascooled to room temperature. Water (2 parts) was added and mixed for18-24 hours and then filtered through a Buchner funnel. The collectedsolid was washed with water (4 parts) and dried under vacuum andnitrogen for 2 days to obtain off-white to light brown solid (DBD), 34 gor about 40% yield.

This method can be modified according by the use of alternatives knownto those of ordinary skill in the art. For example, a relativelylow-molecular-weight monoprotic acid such as formic acid or propanoicacid can replace acetic acid.

For the preparation of dianhydrogalactitol from dibromodulcitol, thereaction is as shown in Scheme 2 (Step 2).

In this method 56 g (2.5 eq) potassium carbonate and THF(tetrahydrofuran) (15 parts) were added to 50 g of DBD (1 eq) and mixed.The mixture was heated to 40° C. and mixed for 18 hours and then cooledto room temperature. The product was filtered through Buchner funnel toremove inorganic solid and washed twice with THF. The filtrate andwashes were collected and concentrated to 4-5 parts with water bath setat 35° C. Heptane (10 parts) was added and mixed for 1-2 hours at roomtemperature. The mixture was filtered through Buchner funnel and washedtwice with heptane. The solid was dried under vacuum and nitrogen for18-24 hours at room temperature to obtain 19 g crude DAG, about 80%yield.

The final step is recrystallization of DAG. THF (20 parts) was added to18.5 g of crude DAG (1 eq) and mixed for 1-2 hours at room temperature.The mixture was filtered through a Buchner funnel to discard solid.Heptane (20 parts) was slowly added and mixed for 2-4 hours at roomtemperature. The mixture was filtered. The solid was dried under vacuumand nitrogen for 18-24 hours at room temperature to obtain 10 g crudeDAG, about 54% yield.

In this method, other nonpolar organic solvents, typically saturatedhydrocarbons such as hexane or octane, can be used in place of heptane.In this methods, other relatively polar but aprotic organic solvents canbe used in place of tetrahydrofuran.

Other alternative methods for preparation of DAG are described below.1,2:5,6-dianhydrodulcitol (also known as DAG) is a compound withmultiple hydroxyl groups and epoxide groups. This characteristicstructure determines instability of this compound because of thetendency of the epoxide ring to open under acid, base or heatconditions. These methods start with dulcitol rather thandibromodulcitol.

In one additional alternative, the 1,6-hydroxy groups on dulcitol(available commercially) are modified to convert to an effective leavinggroup such as Br, OTf (triflate or trifluoromethane sulfonate), or OTs(tosylate), and then, using an inorganic weak base, the target compoundDAG is prepared through an intramolecular S_(N)2 reaction as shown inScheme 3.

In this alternative, a preferred leaving group is Br. For Step 1 asshown in Scheme 3, there are four possible methods to prepare theintermediate with four hydroxyl groups and two leaving groups (e.g.,Br). These methods are as follows when Br is to be introduced as theleaving group. This intermediate is designated Compound 1a below:

Method A for Preparation of Intermediate

The conditions are 45-48% HBr aq/P/Br₂/70° C., 5-7 hr. The procedure isas follows: Add phosphorus to aqueous solution of 45-48% HBr at 0° C.and carefully add Br₂ dropwise to make HBr solution with concentrationabout 60-70%. Add dulcitol and heat to 70° C. in a closed reactor for5-7 hours. After the completion of reaction, cool the reaction mass toroom temperature and pour into ice water to obtain the crude compound 1a(the intermediate referred to above). For purification, a polar solventwithout a nucleophilic property, such as 2-chloromethane/t-butanol or2-chloromethane/isopropyl alcohol is used for recrystallization. Due tothe instability of compound 1, (hydrolysis under D₂O/room temp orH₂O/reverse) back to dulcitol, it is important to avoid hydrolysis sothat Compound 1a is not converted back to dulcitol in the course ofrecrystallization or column chromatography.

This method has high yield (˜80%) with good repeatability. However, itrequires the use of corrosive HBr solution and volatile, toxic Br₂.

Method B for Preparation of Intermediate

The conditions are 62% HBr aq/P/Br₂/70° C., 5-7 hr. The procedure is asfollows: Add dulcitol to 62% HBr aqueous solution. Heat to 70° C. in aclosed reactor for 5-7 hours. After the completion of reaction, cool thereaction mass to room temperature and pour into ice water to obtain thecrude Compound 1a. For purification, use mixed solvents of2-chloromethane/t-butanol or 2-chloromethane/isopropyl alcohol forrecrystallization.

This method uses commercial 62% HBr aqueous solution to simplify theprocedures and avoid high risk using Br₂. However, the reaction needshighly corrosive HBr solution and volatile, toxic Br₂.

Method C for Preparation of Intermediate

The conditions are 33% HBr in HOAc/r.t., 5-7 hr. The procedure is asfollows: Add dulcitol to 33% HBr solution in acetic acid, mix for 5-7hours at room temperature. Add methanol and mix for 15 hours.Concentrate under vacuum to remove most of the solvent. Pour theremaining solution into ice water to collect the crude Compound 1a. Forpurification, use mixed solvents of 2-chloromethane/t-butanol or2-chloromethane/isopropyl alcohol for recrystallization.

This alternative uses commercial 33% HBr acetic solution with simpleprocedures. However, the reaction requires use of highly corrosive HBrsolution.

Method D for Preparation of Intermediate

The conditions are: CBr₄/Ph₃P/pyridine or DMF/r.t., 15-18 hr. Theprocedure is as follows: Dissolve dulcitol in pyridine ordimethylformamide (DMF) at room temperature. Add CBr₄ and Ph₃P insequence and mix for 15-18 hours at room temperature. After thecompletion of reaction, concentrate under vacuum to remove solvent andchloroform formed from reaction. Wash the remaining solid several timeswith dichloromethane to remove triphenylphosphine byproduct. Forpurification, use mixed solvents of 2-chloromethane/t-butanol or2-chloromethane/isopropyl alcohol for recrystallization.

The advantages of this method are moderate reaction conditions withoutusing HBr or Br₂. However, the reaction will produce triphenylphosphinebyproduct which will affect the purity of Compound 1a.

As indicated above, the 1,6-hydroxy groups can be modified by otherleaving groups, such as TfO— (Compound 1b) or TsO— (Compound 1c) inStep 1. Since there are several hydroxyl groups in dulcitol, it isimportant to control the reagent quantity during sulfonylation reaction.

For the preparation of Compound 1b or Compound 1c, the conditions are:TsCl or Tf₂O/Pyridine/0° C., 4-8 hr. The procedure is as follows:Dissolve dulcitol in pyridine. Add TsCl or Tf₂O at 0° C. and mix for15-18 hours. After the completion of reaction, concentrate under vacuumto remove solvent. Pour the remaining solution into ice water to obtaincrude Compound 1b or Compound 1c. For purification, use mixed solventsof 2-chloromethane/t-butanol or 2-chloromethane/isopropyl alcohol forrecrystallization.

Typically, this method generates an equivalent of the pyridine salt ofp-toluenesulfonic acid or trifluoromethanesulfonic acid. Removal ofthese byproducts is important in yielding Compound 1b or Compound 1c inhigh purity.

For Step 2 of this procedure, resulting in DAG, one alternative,described above, uses conditions of K₂CO₃/t-BuOH. However, this may notbe optimum in larger-scale preparations. Under small scale conditions(0.5 g), moderate yield (˜70%) can be achieved. The yield wassignificantly reduced to ˜40% when the scale was 4 g. Although Applicantdoes not intend to be bound by this supposition, this may result fromthe formation of an azeotropic mixture of DAG and t-butanol with a lowboiling point. Therefore, as indicated above, this may not beefficiently scalable for preparations >1 g.

Under alkaline conditions, Compound 1a, 1b, or 1c, described above (theintermediate prior to the formation of DAG) may undergo a series of sidereactions shown in Scheme 4.

These side reactions may include intermolecular reactions due tonucleophilic reagent of alkaline or solvent (alcohol or water) toproduce side product I; or intra-molecular attack by hydroxyl group toproduce byproducts (I-IV) with furan ring, formed more rapidly comparedto epoxide. Therefore, it is critical to select or control the step 2reaction conditions to prevent the occurrence of side reactions to theextent possible.

In this alternative, it is generally preferred to use an inorganicalkali (such as K₂CO₃, Cs₂CO₃, or other inorganic carbonates) and apolar nonionic solvent favorable for S_(N)2 reaction to produce DAG astarget product. The inorganic alkali used is not nucleophilic and doesnot cause intermolecular nucleophilic substitution. The polar nonionicsolvent not only provides better solubility for inorganic alkali and amore polar alcohol reactant 1a, 1b, or 1c, but also will not cause sidereactions because of the lack of nucleophilicity. In addition, replacingthe reported t-butanol with this solvent, the co-distillation (azeotropeformation) between DAG and t-butanol can be avoided. This will resolvethe scale-up issue. The specific conditions are as follows:K₂CO₃/DMF/r.t., 5-7 hr. The procedure is as follows: Dissolve theproduct from Step 1 (i.e., Compound 1a, Compound 1b, or Compound 1c), ina polar nonionic solvent such as DMF. Add K₂CO₃ or the other inorganiccarbonate and mix at room temperature for 5-7 hours. After completion ofthe reaction, add p-toluenesulfonic acid to neutralize potassiumcarbonate or other inorganic carbonate. Concentrate under vacuum toremove solvent. Wash the remaining solid with water to remove theinorganic impurities. For purification, add ether to crude material andmix vigorously. Filter the slurry to obtain target DAG.

In another alternative, the synthetic route for dianhydrogalactitol isas shown in Scheme 5.

In the synthetic route of Scheme 5, the process starts with substitutionof 1,6 hydroxy groups with bromine and other hydroxyl groups with acetylgroups yielding compound 4, which is then reacted with zinc to formdouble bonds through an elimination reaction with a molecular conjugatedbase such as sodium methoxide. The protective acetyl group is removed toyield compound 5. Finally, through the use of the Sharpless epoxidationreaction, the target compound DAG is formed. Typically, the substitutionof the 1,6 hydroxy groups is performed with reaction with acetylbromide; alternatively, other bromide-substituted acyl compounds can beused. Typically, the acetylation of the hydroxy groups other than the1,6-hydroxy groups is performed with acetic anhydride in pyridine.

Another embodiment of the invention provides recrystallizeddianhydrogalactitol in a four-stage process. This four-stage processbegins with dibromodulcitol. This four-stage process produceshigh-purity dianhydrogalactitol and can be scaled up for the productionof large quantities of high-purity recrystallized dianhydrogalactitol.This embodiment has a number of advantages. It utilizes commerciallyavailable hydrobromic acid in acetic acid at a concentration of 33% to48% to allow reaction with dulcitol to proceed at ambient roomtemperature or at an elevated temperature up to 50° C. This avoids thenecessity of using high concentrations of hydrobromic acid (>56%) underhigh temperature and high pressure, which requires handling of aconcentrated hydrobromic acid solution that is hazardous and verycorrosive to piping and reactors. The use of such a concentratedhydrobromic acid solution requires use of a specially designed reactorthat is protected from corrosive hydrobromic acid. Such a reactor isexpensive and the requirement for its use makes the process lessflexible for changing the scale of the synthesis. This embodiment avoidsthe requirement for replacement of a specialized cation exchange resinwhich is available from limited suppliers and requires pretreatmentbefore use; in addition, special equipment and procedures are requiredfor washing the cation exchange resin with sodium hydroxide. This isavoided by use of this embodiment. The new process described in thisembodiment is easy to scale up with flexibility of batch size and lowermanufacturing cost. This embodiment is described below in terms of a100-g batch; it has already been scaled up to a 200-g batch with purityof >99.0%. Details of this embodiment are provided below.

The first stage of this process is directed to the conversion ofdulcitol to dibromodulcitol. In the first stage of this four-stageprocess, a 20-liter reactor is used with the outlet connected to a trapflask containing 1 N NaOH solution. Hydrobromic acid solution (33%) ischarged at room temperature in one portion (9.7 liters, 2.1 equivalents,2.02 parts). Dulcitol (4.8 kg, 26.35 mol, 1.0 equivalents) is chargedslowly in small portions through the manway of the reactor withagitation. The reaction mixture is heated to 40° C. and then agitatedfor 18-24 hours at 40° C. The reaction mixture is cooled to roomtemperature to yield an off-white suspension. An 0.5 mL sample is takenfor in-process analysis; the dulcitol content by HPLC is to be limitedto <0.02%. In this stage, HBr vapors are present during the charging ofthe hydrobromic acid solution. Care should be taken to minimize contactwith air during charging. Any plastic parts on the reactor will degradeon contact with the HBr vapors. HBr vapors will also be present duringthe charging with the solid dulcitol. Care should be taken to minimizeescape of these vapors during the charging with the solid dulcitol.

The second stage is a work-up of the dibromodulcitol. In this stage,D.I. water is charged at ambient temperature (9.6 liters, 2 parts) inabout 30 minutes. The mixture is agitated at ambient temperature for 24hours (white solid suspension). The reaction mixture is filtered and thesolids are washed with 2×5 L of D.I. water. The solids are dried atambient temperature under nitrogen for 12 hours. Suction is applied tothe filter to increase nitrogen flow through the solid. The solids arewashed with 2×4 L of methyl t-butyl ether (MTBE). The solids are driedat ambient temperature under nitrogen for 48-72 hours. Suction isapplied to the filter to increase nitrogen flow through the solid. Theyield is 3.2 kg dibromodulcitol (38%). Characterization testing resultsare: total impurities, 10.8%; residual HOAc (acetic acid), 0.67%; watercontent, 2.14%.

The third stage is the conversion of dibromodulcitol (DBD) to crudedianhydrogalactitol (DAG). In the third stage, a nitrogen-purged 1-literthree-neck round bottom flask is used. The round-bottom flask isequipped with a magnetic stirrer, nitrogen thermometer, and condenser.DBD (50 g, 0.162 mol, 1.0 equivalents) is charged to the reaction flask.Potassium carbonate (56 g, 0.405 mol, 2.5 equivalents) is then chargedto the reaction flask. Tetrahydrofuran (THF) (750 mL, 15 parts) is thencharged into the reaction flask and agitation of the white suspension isstarted. Heating of the reaction mixture is then begun and thetemperature is adjusted to 40° C. The reaction mixture is maintained at40° C. for 18 hours and then cooled to ambient temperature. An 0.5 mLsample is taken for in-process analysis; the DAG content is assessed byHPLC (limit: >30%). The reaction mixture is then filtered to remove theinorganic solids. The inorganic solids are washed using 2×125 mL (2.5parts) of THF. Then, the THF washes are combined with the filtrate andconcentrated down to about 150-200 mL (3-4 parts) with bath temperatureset at 35° C. The resulting suspension is then cooled to 4° C. The whitesuspension is then agitated for 24 hours at 4° C. The solids are thenfiltered and washed with 100 mL (2 parts) MTBE. The white solids arethen dried at ambient temperature under nitrogen for a minimum of 18hours. Suction is applied to the filter to increase nitrogen flowthrough the solid. The yield is 13.7 crude DAG (68%). Characterizationtesting results are: total impurities, 1.44%; residual HOAc/MTBE, notdetectable; residual THF, 0.23%.

The fourth stage is the recrystallization of the DAG. In the fourthstage, a nitrogen-purged 1-liter three-neck round bottom flask is used.The round-bottom flask is equipped with a magnetic stirrer, nitrogenthermometer, and condenser. Crude DAG (11 g) is charged into thereaction flask at room temperature. Acetone (275 mL, 25 parts) ischarged into a reaction flask at ambient temperature and agitation isstarted. The reaction mixture, which is slightly cloudy, is agitated atambient temperature for 30 minutes. The insoluble solids are filteredoff and the acetone filtrate is collected. The acetone filtrate is thencharged back to the reaction flask and concentrated down to about 25 mL(about 2 parts) with the bath temperature set at 30° C. The reactionmixture is then cooled to −20° C. and then agitated for 24 hours at −20°C.; the reaction mixture is a white suspension. The solids are filteredand washed with 44 mL (4 parts) MTBE. The solids are dried at ambienttemperature under nitrogen for a minimum of 18 hours. Suction is appliedto the filter to increase nitrogen flow through the solid. 10 g whitesolid of DAG is yielded (91%). Characterization testing results are:total impurities, 0.63%; residual HOAc/THF/MTBE, not detectable;residual acetone: 0.14%; water content, 2.14%.

This method is suitable for scaling up and for the production of largequantities of recrystallized dianhydrogalactitol. This method can beapplied to other hexitols.

In general, as applied to the synthesis of a dianhydrohexitol, themethod comprises the steps of:

(1) converting a hexahydroxyl-substituted sugar alcohol to a dibromoderivative of the hexahydroxyl-substituted sugar alcohol by reaction ofthe dulcitol with hydrobromic acid for from about 18 hours to about 36hours at an elevated temperature;

(2) adding the product of step (1) to water, agitating the product ofstep (1) added to water for from about 18 hours to about 36 hours,filtering the mixture of the product of step (1) and water, washing themixture with a large volume of water, drying the solid product undernitrogen, and then subsequently washing the dried solid product with alarge volume of an aliphatic ether;

(3) reacting the product of step (b) with a carbonate of an alkali metalin a polar aprotic solvent at an elevated temperature;

(4) filtering the product of step (3) to remove the solids;

(5) washing the solids removed in step (4) with a polar aprotic solventand combining the washings with the solids removed in step (4);

(6) concentrating the combination of the washings with the solids ofstep (5) to a volume that is approximately from about 0.20 to about 0.27of the volume of polar aprotic solvent used in step (3) at a temperatureof from about 30° C. to about 40° C.;

(7) agitating the concentrated product of step (6) for from about 18hours to about 36 hours at a temperature of from about 0° C. to about10° C.;

(8) washing the product of step (7) with an aliphatic ether;

(9) drying the washed product of step (8) under nitrogen; and

(10) recrystallizing the product of step (9) by:

-   -   (a) dissolving the product of step (9) in acetone;    -   (b) filtering off insoluble solids remaining after dissolving        the product of step (9) in acetone;    -   (c) concentrating the solution of step (10)(a) down to a volume        of about 0.07 to about 0.12 of the original volume of acetone;    -   (d) cooling the concentrated solution of step (10)(c) to about        −20° C. to generate solid recrystallized dianhydrohexitol and        agitating the suspension of solid recrystallized        dianhydrohexitol for from about 18 hours to about 36 hours;    -   (e) filtering the solids of step (10)(d) and washing the solids        with a large volume of an aliphatic ether; and    -   (f) drying the washed solids of step (10)(e) under nitrogen to        produce a solid recrystallized dianhydrohexitol.

Accordingly, a method for synthesizing and recrystallizingdianhydrogalactitol that is suitable for large-scale preparation ofpurified dianhydrogalactitol comprises the steps of:

(1) converting dulcitol to dibromodulcitol by reaction of the dulcitolwith hydrobromic acid for from about 18 hours to about 36 hours at anelevated temperature;

(2) adding the product of step (a) to water, agitating the product ofstep (1) added to water for from about 18 hours to about 36 hours,filtering the mixture of the product of step (1) and water, washing themixture with a large volume of water, drying the solid product undernitrogen, and then subsequently washing the dried solid product with alarge volume of an aliphatic ether;

(3) reacting the product of step (2) with a carbonate of an alkali metalin a polar aprotic solvent at an elevated temperature;

(4) filtering the product of step (3) to remove the solids;

(5) washing the solids removed in step (4) with a polar aprotic solventand combining the washings with the solids removed in step (4);

(6) concentrating the combination of the washings with the solids ofstep (5) to a volume that is approximately from about 0.20 to about 0.27of the volume of polar aprotic solvent used in step (3) at a temperatureof from about 30° C. to about 40° C.;

(7) agitating the concentrated product of step (6) for from about 18hours to about 36 hours at a temperature of from about 0° C. to about10° C.;

(8) washing the product of step (7) with an aliphatic ether;

(9) drying the washed product of step (8) under nitrogen; and

(10) recrystallizing the product of step (9) by:

-   -   (a) dissolving the product of step (9) in acetone;    -   (b) filtering off insoluble solids remaining after dissolving        the product of step (9) in acetone;    -   (c) concentrating the solution of step (10)(a) down to a volume        of about 0.07 to about 0.12 of the original volume of acetone;    -   (d) cooling the concentrated solution of step (10)(c) to about        −20° C. to generate solid recrystallized dianhydrogalactitol and        agitating the suspension of solid recrystallized        dianhydrogalactitol for from about 18 hours to about 36 hours;    -   (e) filtering the solids of step (10)(d) and washing the solids        with a large volume of an aliphatic ether; and    -   (f) drying the washed solids of step (10)(e) under nitrogen to        produce solid recrystallized dianhydrogalactitol.

Typically, the elevated temperature of step (1) is from about 35° C. toabout 45° C. Preferably, the elevated temperature of step (1) is about40° C.

Typically, in step (1), the dulcitol is reacted with hydrobromic acidfrom about 18 hours to about 24 hours.

Typically, the aliphatic ether of step (2) is selected from the groupconsisting of methyl t-butyl ether, dimethyl ether, methyl ethyl ether,diethyl ether, dipropyl ether, methyl propyl ether, and ethyl propylether. Preferably, the aliphatic ether of step (2) is methyl t-butylether.

Typically, in step (2), the mixture of the product of step (1) added towater is agitated for about 24 hours.

Typically, the polar aprotic solvent of step (3) is tetrahydrofuran.Typically, the carbonate of the alkali metal of step (3) is selectedfrom the group consisting of lithium carbonate, sodium carbonate, andpotassium carbonate. Preferably, the carbonate of the alkali metal ofstep (3) is potassium carbonate. Typically, the elevated temperature ofstep (3) is from about 35° C. to about 45° C. Preferably, the elevatedtemperature of step (3) is about 40° C.

Typically, the temperature of step (6) is about 35° C.

Typically, the temperature of step (7) is about 4° C. Typically, in step(7), the concentrated product of step (6) is agitated for about 24hours.

Typically, the aliphatic ether of step (8) is selected from the groupconsisting of methyl t-butyl ether, dimethyl ether, methyl ethyl ether,diethyl ether, dipropyl ether, methyl propyl ether, and ethyl propylether. Preferably, the aliphatic ether of step (8) is methyl t-butylether.

Typically, in step (10)(c), the solution of step (10)(a) is concentrateddown to about 0.09 of the original volume of acetone. Typically, theagitation of step (10)(d) is performed for about 24 hours.

Typically, the aliphatic ether of step (10)(e) is selected from thegroup consisting of methyl t-butyl ether, dimethyl ether, methyl ethylether, diethyl ether, dipropyl ether, methyl propyl ether, and ethylpropyl ether. Preferably, the aliphatic ether of step (10)(e) is methylt-butyl ether.

Typically, the drying of step (10)(f) is performed for a minimum ofabout 18 hours.

Typically, the recrystallized dianhydrogalactitol produced by the methoddescribed above, with steps (1)-(10), has total impurities of less thanabout 0.65%. Typically, the recrystallized dianhydrogalactitol producedby the method described above, with steps (1)-(10), has no detectableacetic acid, tetrahydrofuran, or methyl t-butyl ether. Typically, therecrystallized dianhydrogalactitol produced by the method describedabove, with steps (1)-(10), has residual acetone of less than about0.15%. Typically, the recrystallized dianhydrogalactitol produced by themethod described above, with steps (1)-(10), has a water content of lessthan about 2.15%.

Another aspect of the invention is purified recrystallizeddianhydrogalactitol produced by the method described above, with steps(1)-(10). Typically, the purified recrystallized dianhydrogalactitol hastotal impurities of less than about 0.65%. Typically, the purifiedrecrystallized dianhydrogalactitol has no detectable acetic acid,tetrahydrofuran, or methyl t-butyl ether. Typically, the purifiedrecrystallized dianhydrogalactitol has residual acetone of less thanabout 0.15%. Typically, the purified recrystallized dianhydrogalactitolhas a water content of less than about 2.15%.

Advantages of the Invention

The present invention provides an improved and efficient method for thesynthesis of substituted hexitols, especially dianhydrogalactitol (DAG).The method of the present invention is readily scalable so that largequantities of dianhydrogalactitol can be prepared for pharmaceutical orother use. The method of the present invention producesdianhydrogalactitol in high yield and free from impurities.

Methods according to the present invention possess industrialapplicability for the synthesis of substituted hexitols, especiallydianhydrogalactitol (DAG), which have uses in pharmacology andelsewhere.

With respect to ranges of values, the invention encompasses eachintervening value between the upper and lower limits of the range to atleast a tenth of the lower limit's unit, unless the context clearlyindicates otherwise. Moreover, the invention encompasses any otherstated intervening values and ranges including either or both of theupper and lower limits of the range, unless specifically excluded fromthe stated range.

Unless defined otherwise, the meanings of all technical and scientificterms used herein are those commonly understood by one of ordinary skillin the art to which this invention belongs. One of ordinary skill in theart will also appreciate that any methods and materials similar orequivalent to those described herein can also be used to practice ortest this invention.

The publications and patents discussed herein are provided solely fortheir disclosure prior to the filing date of the present application.Nothing herein is to be construed as an admission that the presentinvention is not entitled to antedate such publication by virtue ofprior invention. Further the dates of publication provided may bedifferent from the actual publication dates which may need to beindependently confirmed.

All the publications cited are incorporated herein by reference in theirentireties, including all published patents, patent applications, andliterature references, as well as those publications that have beenincorporated in those published documents. However, to the extent thatany publication incorporated herein by reference refers to informationto be published, applicants do not admit that any such informationpublished after the filing date of this application to be prior art.

As used in this specification and in the appended claims, the singularforms include the plural forms. For example the terms “a,” “an,” and“the” include plural references unless the content clearly dictatesotherwise. Additionally, the term “at least” preceding a series ofelements is to be understood as referring to every element in theseries. The inventions illustratively described herein can suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the future shown anddescribed or any portion thereof, and it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the inventions herein disclosedcan be resorted by those skilled in the art, and that such modificationsand variations are considered to be within the scope of the inventionsdisclosed herein. The inventions have been described broadly andgenerically herein. Each of the narrower species and subgenericgroupings falling within the scope of the generic disclosure also formpart of these inventions. This includes the generic description of eachinvention with a proviso or negative limitation removing any subjectmatter from the genus, regardless of whether or not the excisedmaterials specifically resided therein. In addition, where features oraspects of an invention are described in terms of the Markush group,those schooled in the art will recognize that the invention is alsothereby described in terms of any individual member or subgroup ofmembers of the Markush group. It is also to be understood that the abovedescription is intended to be illustrative and not restrictive. Manyembodiments will be apparent to those of in the art upon reviewing theabove description. The scope of the invention should therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled. Thoseskilled in the art will recognize, or will be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the invention described. Such equivalents are intended tobe encompassed by the following claims.

What is claimed is:
 1. A method for synthesizing and recrystallizing adianhydrohexitol comprising the steps of: (a) converting ahexahydroxyl-substituted sugar alcohol to a dibromo derivative of thehexahydroxyl-substituted sugar alcohol by reaction of the dulcitol withhydrobromic acid for from about 18 hours to about 36 hours at anelevated temperature; (b) adding the product of step (a) to water,agitating the product of step (a) added to water for from about 18 hoursto about 36 hours, filtering the mixture of the product of step (a) andwater, washing the mixture with a large volume of water, drying thesolid product under nitrogen, and then subsequently washing the driedsolid product with a large volume of an aliphatic ether; (c) reactingthe product of step (b) with a carbonate of an alkali metal in a polaraprotic solvent at an elevated temperature; (d) filtering the product ofstep (c) to remove the solids; (e) washing the solids removed in step(d) with a polar aprotic solvent and combining the washings with thesolids removed in step (d); (f) concentrating the combination of thewashings with the solids of step (e) to a volume that is approximatelyfrom about 0.20 to about 0.27 of the volume of polar aprotic solventused in step (c) at a temperature of from about 30° C. to about 40° C.;(g) agitating the concentrated product of step (f) for from about 18hours to about 36 hours at a temperature of from about 0° C. to about10° C.; (h) washing the product of step (g) with an aliphatic ether; (i)drying the washed product of step (h) under nitrogen; and (j)recrystallizing the product of step (i) by: (i) dissolving the productof step (i) in acetone; (ii) filtering off insoluble solids remainingafter dissolving the product of step (i) in acetone; (iii) concentratingthe solution of step (j)(i) down to a volume of about 0.07 to about 0.12of the original volume of acetone; (iv) cooling the concentratedsolution of step (j)(iii) to about −20° C. to generate solidrecrystallized dianhydrohexitol and agitating the suspension of solidrecrystallized dianhydrohexitol for from about 18 hours to about 36hours; (v) filtering the solids of step (j)(iv) and washing the solidswith a large volume of an aliphatic ether; and (vi) drying the washedsolids of step (j)(v) under nitrogen to produce a solid recrystallizeddianhydrohexitol.
 2. A method for synthesizing and recrystallizingdianhydrogalactitol comprising the steps of: (a) converting dulcitol todibromodulcitol by reaction of the dulcitol with hydrobromic acid forfrom about 18 hours to about 36 hours at an elevated temperature; (b)adding the product of step (a) to water, agitating the product of step(a) added to water for from about 18 hours to about 36 hours, filteringthe mixture of the product of step (a) and water, washing the mixturewith a large volume of water, drying the solid product under nitrogen,and then subsequently washing the dried solid product with a largevolume of an aliphatic ether; (c) reacting the product of step (b) witha carbonate of an alkali metal in a polar aprotic solvent at an elevatedtemperature; (d) filtering the product of step (c) to remove the solids;(e) washing the solids removed in step (d) with a polar aprotic solventand combining the washings with the solids removed in step (d); (f)concentrating the combination of the washings with the solids of step(e) to a volume that is approximately from about 0.20 to about 0.27 ofthe volume of polar aprotic solvent used in step (c) at a temperature offrom about 30° C. to about 40° C.; (g) agitating the concentratedproduct of step (f) for from about 18 hours to about 36 hours at atemperature of from about 0° C. to about 10° C.; (h) washing the productof step (g) with an aliphatic ether; (i) drying the washed product ofstep (h) under nitrogen; and (j) recrystallizing the product of step (i)by: (i) dissolving the product of step (i) in acetone; (ii) filteringoff insoluble solids remaining after dissolving the product of step (i)in acetone; (iii) concentrating the solution of step (j)(i) down to avolume of about 0.07 to about 0.12 of the original volume of acetone;(iv) cooling the concentrated solution of step (j)(iii) to about −20° C.to generate solid recrystallized dianhydrogalactitol and agitating thesuspension of solid recrystallized dianhydrogalactitol for from about 18hours to about 36 hours; (v) filtering the solids of step (j)(iv) andwashing the solids with a large volume of an aliphatic ether; and (vi)drying the washed solids of step (j)(v) under nitrogen to produce solidrecrystallized dianhydrogalactitol.
 3. The method of claim 2 wherein theelevated temperature of step (a) is from about 35° C. to about 45° C. 4.The method of claim 3 wherein the elevated temperature of step (a) isabout 40° C.
 5. The method of claim 2 wherein, in step (a), the dulcitolis reacted with hydrobromic acid from about 18 hours to about 24 hours.6. The method of claim 2 wherein the aliphatic ether of step (b) isselected from the group consisting of methyl t-butyl ether, dimethylether, methyl ethyl ether, diethyl ether, dipropyl ether, methyl propylether, and ethyl propyl ether.
 7. The method of claim 6 wherein thealiphatic ether of step (b) is methyl t-butyl ether.
 8. The method ofclaim 2 wherein, in step (b), the mixture of the product of step (a)added to water is agitated for about 24 hours.
 9. The method of claim 2wherein the polar aprotic solvent of step (c) is tetrahydrofuran. 10.The method of claim 2 wherein the carbonate of the alkali metal of step(c) is selected from the group consisting of lithium carbonate, sodiumcarbonate, and potassium carbonate.
 11. The method of claim 10 whereinthe carbonate of the alkali metal of step (c) is potassium carbonate.12. The method of claim 2 wherein the elevated temperature of step (c)is from about 35° C. to about 45° C.
 13. The method of claim 12 whereinthe elevated temperature of step (c) is about 40° C.
 14. The method ofclaim 2 wherein the polar aprotic solvent of step (e) istetrahydrofuran.
 15. The method of claim 2 wherein the temperature ofstep (f) is about 35° C.
 16. The method of claim 2 wherein thetemperature of step (g) is about 4° C.
 17. The method of claim 2wherein, in step (g), the concentrated product of step (f) is agitatedfor about 24 hours.
 18. The method of claim 2 wherein the aliphaticether of step (h) is selected from the group consisting of methylt-butyl ether, dimethyl ether, methyl ethyl ether, diethyl ether,dipropyl ether, methyl propyl ether, and ethyl propyl ether.
 19. Themethod of claim 18 wherein the aliphatic ether of step (h) is methylt-butyl ether.
 20. The method of claim 2 wherein in step (j)(iii), thesolution of step (j)(i) is concentrated down to about 0.09 of theoriginal volume of acetone.
 21. The method of claim 2 wherein theagitation of step (j)(iv) is performed for about 24 hours.
 22. Themethod of claim 2 wherein the aliphatic ether of step (j)(v) is selectedfrom the group consisting of methyl t-butyl ether, dimethyl ether,methyl ethyl ether, diethyl ether, dipropyl ether, methyl propyl ether,and ethyl propyl ether.
 23. The method of claim 22 wherein the aliphaticether of step (j)(v) is methyl t-butyl ether.
 24. The method of claim 2wherein the drying of step (j)(vi) is performed for a minimum of about18 hours.
 25. The method of claim 2 wherein the recrystallizeddianhydrogalactitol produced by the process has total impurities of lessthan about 0.65%.
 26. The method of claim 2 wherein the recrystallizeddianhydrogalactitol produced by the method has no detectable aceticacid, tetrahydrofuran, or methyl t-butyl ether.
 27. The method of claim2 wherein the recrystallized dianhydrogalactitol produced by the methodhas residual acetone of less than about 0.15%.
 28. The method of claim 2wherein the recrystallized dianhydrogalactitol produced by the methodhas a water content of less than about 2.15%.
 29. Purifiedrecrystallized dianhydrogalactitol produced by the method of claim 2.30. The purified recrystallized dianhydrogalactitol of claim 29 that hastotal impurities of less than about 0.65%.
 31. The purifiedrecrystallized dianhydrogalactitol of claim 29 that has no detectableacetic acid, tetrahydrofuran, or methyl t-butyl ether.
 32. The purifiedrecrystallized dianhydrogalactitol of claim 29 that has residual acetoneof less than about 0.15%.
 33. The purified recrystallizeddianhydrogalactitol of claim 29 that has a water content of less thanabout 2.15%.